Fig. 8 | Nature Communications

Fig. 8

From: High mitogenic stimulation arrests angiogenesis

Fig. 8

High-mitogenic stimulation arrests angiogenesis. a Proposed bell-shaped dose–response to mitogenic stimulation regulated by Notch, VEGF, ERK, and p21. At very low levels of VEGF signalling, ECs are quiescent, since they have Notch signalling, which supresses ERK activity and cell proliferation. Stalk cells have a properly balanced level of Notch and VEGF signalling, resulting in an ERK activity level ideal for cell proliferation. Tip cells have high-VEGF signalling, and low-Notch signalling, resulting in cumulative high ERK activity, which induces p21, cell-cycle arrest, and cell sprouting/migration. b Illustration showing the identified distribution of the indicated cellular markers in tip, stalk and quiescent ECs. Colours indicate P-ERK (red cytoplasm), Esm1/p21 (green nuclei), KI67 (blue if positive and dark grey if negative). Colour intensity indicates the observed strength of signal or expression. At the angiogenic front, endothelial tip cells receive a higher mitogenic stimulus from VEGF. This induces ERK activation and high expression of Esm1 and p21. Higher Notch signalling in stalk cells attenuates the VEGF-induced ERK and p21 activation. In the more mature and quiescent vascular areas, most ECs have very low P-ERK levels and have already exited the cell cycle (KI67−) because they are exposed to less VEGF. However, these cells still have active Notch signalling, which is important for maintaining their quiescence. c When Dll4/Notch signalling is inhibited, angiogenic stalk cells display a tip-cell like profile and upregulate Esm1 expression and ERK phosphorylation. This leads to p21 expression, which induces the cell-cycle arrest of stalk-cells, and compromises the subsequent proliferation and development of vessels toward the hypoxic tissue area. Impairment of Dll4/Notch signalling in more mature and quiescent ECs (grey), produces a distinct effect; here, the increase in P-ERK after Dll4/Notch inhibition is more moderate and productive, and ECs enter the cell cycle even when VEGF signalling is low

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